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Related Concept Videos

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T Cell Types and Functions

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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
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Related Experiment Video

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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
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Role of ADAM10 and ADAM17 in Regulating CD137 Function.

Jana Seidel1, Sinje Leitzke1, Björn Ahrens1

  • 1Department of Dermatology, University of Kiel, 24105 Kiel, Germany.

International Journal of Molecular Sciences
|April 3, 2021
PubMed
Summary

Researchers discovered that A Disintegrin and Metalloproteinase (ADAM)10, not a splice variant, generates soluble CD137 (sCD137). This shedding process, influenced by phosphatidylserine and Anoctamin-6, impacts T cell proliferation and immunotherapy.

Keywords:
ADAM10ADAM17Anoctamin-6CD137T cell proliferationcancer

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Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Human CD137 (4-1BB) and its ligand CD137L (4-1BBL) are key immune regulators involved in inflammation, autoimmunity, and oncology.
  • Elevated soluble CD137 (sCD137) levels are observed in rheumatoid arthritis and malignancies, previously thought to be a splice variant.
  • CD137/CD137L interactions mediate crucial bidirectional cellular responses.

Purpose of the Study:

  • To investigate the mechanism of soluble CD137 (sCD137) generation.
  • To elucidate the role of specific enzymes and cellular components in sCD137 release.
  • To understand the functional implications of sCD137 in immune responses and potential therapeutic strategies.

Main Methods:

  • Utilized transfected cell lines and primary T cells to study CD137 shedding.
  • Employed ADAM10 inhibition to assess its role in sCD137 generation.
  • Investigated the influence of phosphatidylserine (PS) and the phospholipid scramblase Anoctamin-6 (ANO6) on ADAM10-mediated shedding.

Main Results:

  • Demonstrated that A Disintegrin and Metalloproteinase (ADAM)10, and potentially ADAM17, are central to sCD137 generation.
  • Showed that ADAM10 inhibition effectively blocked sCD137 release.
  • Confirmed that Anoctamin-6 (ANO6) modulates ADAM10 function by trafficking phosphatidylserine, influencing constitutive and stimulated sCD137 shedding, and that sCD137 augments T cell proliferation.

Conclusions:

  • Soluble CD137 (sCD137) is generated through enzymatic shedding by ADAM10, not alternative splicing.
  • Phosphatidylserine exposure and Anoctamin-6 play critical roles in regulating this shedding process.
  • These findings offer new insights into CD137/CD137L immune response regulation and impact immunotherapeutic approaches.